3-endolyl-2-aminoethylketones and their preparation



3,037,991 S-ENDGLYL-Z-AWNGETHYLIETGNES AND Tim PREPARATION JacobSzmuszlrevicz, Portage Township, Kalamazoo County, Mich, assignor to TheUpjohn Company, Kalamazoo, Mich, a corporation of Michigan No Drawing.Filed Get. 29, 1958, er. No. 770,275

7 Claims. (Cl. 260-319) The present invention relates to a novel processfor the preparation of 3-indolyl Z-amirioethyl ketones and moreespecially to the preparation of 1-hydro-3-indolyl Z-aminoethyl ketonefree bases, 1-alkyl-3-indolyl Z-aminoethyl free bases,1-aminomethyl-3-indolyl Z-aminoethyl ketone 'free bases, and additioncompounds thereof such as acid addition salts, quaternary ammoniumsalts, amine oxides, and amine oxide-acid addition salts. The inventionalso relates to novel 1-hydro-3-indolyl 2-aminoethyl ketone quaternaryammonium salts, and to novel 1-alkyl-3-indolyl 2-aminoethyl ketone freebases, l-aminomethyl-3-indolyl Z-aminoethyl ketone free bases, andaddition compounds thereof. This application is a continuation, in partof application Serial No. 529,911, filed August 22, '1955, nowabandoned.

The term hydro as used herein indicates the presence of hydrogen in the1-position in contrast to the l-alkyl and l-aminomethyl substituents.

The l-alkyl-3-indolyl 2-aminoethyl ketones and l-am-inomethyl-3-indolylZ-aminoeth'yl ketones of the present invention are produced by reactinga l-alkyl-3-acylindole or 1-hydro-3-acylindole, respectively, containinga hydrogen atom alpha to the carbonyl group, with the appropriatequantity of an aliphatic aldehyde and a basic nitrogen compound asrepresented by ammonia or a primary or a secondary amine. The acylsubstitucnt of the starting indo'le is from an alkanoic acid such asacetic acid, propionic acid, butyric acid, isobutyric acid, Valerieacid, isovaleric acid, Z-ethylbutyric acid, Z-butylhexanoic acid, andthe like. The use of ammonia results in the preparation of a primaryamino-ketone and the use of a primary or secondary amine results in theproduction of a secondary or tertiary amino-ketone, respectively.

The 1-hydro-3-indolyl Z-aminoethyl ketones of the present invention areproduced by subjecting the l-aminomethyl-S-indolyl Z-aminoethyl ketonesto alkaline hydrolysis.

The 3-indolyl 2-aminoethyl ketones produced by the novel process of thepresent invention can for the most part be represented by the followinggeneral formula:

T t an Ra Rs N wherein R, R and R represent hydrogen and a loweralkylradical containing from 1 to 4 carbon atoms such as methyl, ethyl,propyl, butyl, isobutyl, and the like. R and R taken individuallyrepresent hydrogen, aryl, aralkyl, and alkyl and together contain notmore than carbon atoms, and R and R taken together 'with 3,037,991Patented June 5, 1962 carbon atoms such as methyl, ethyl, propyl, butyl,amyl, hexyl, and the like, and X further represents I R1-CH R5 a whereinR R and R have the same values as noted above.

The 4-, 5-, 6-, and 7-positions of the benzene ring can include suchsubstituents as hydrogen; hydroxy; halogen, e.g., chlorine, bromine, andthe like; a benzyloxy radical, e.g., benzyloxy, benzhydryloxy, and thelike; a loweralkoxy radical containing up to nine carbon atoms, e.g.,methoxy, ethoxy, butoxy, octoxy, and the like; an acyloxy radicalwherein the acyl substituent is from an organic carboxylic acidcontaining from one to eight carbon atoms, e.g., acetoxy, propionoxy,capryloxy, and the like. The 4-, 5-, 6-, and 7-position substituents canbe alike or different but it is understood that hydrogen is located inthe positions not occupied by other substituents. 'Ihe Z-position can beoccupied by' hydrogen, a lower-alkyl radical containing from one toeight carbon atoms, e.g., methyl, ethyl, propyl, octyl, and the like; anaralkyl radical, e.g., benzyl, phenethyl, and the like; an aryl radical,e.g., phenyl, naphthyl, and the like.

'The various 2-, 4-, 5-, 6-, and 7-substituted indoles 'which can beemployed as starting compounds for the preparation of the 3-acylindolescan be prepared by utilizing the procedures outlined in U.S. Patent2,825,734.

The starting 3-acylindoles can be preparedby the processes outlined inHeterocyclic Compounds, Elderfield volume 3 page 44, 1952, John Wileyand Sons, Inc. For example, 3-indolyl methyl ketone can be prepared byreacting acetyl chloride With 3'-indolylr nagnesiurn iodide;3-(2-methylindolyl) methyl ketone can be prepared by reactingZ-methylindole with acetic anhydride and sodium acetate.

1-alkyl-3-acylindoles can be prepared by utilizing the procedure ofBaker, J. Chem. Soc. 1940, 458-60. For example, 1-alkyl-3-acylindolescan be preparedby reacting a 1-hydro-3-acylindole with an alkyl halidein the presence of an alkali-metal alkoxide.

In carrying out the process of the present invention for the preparationof the novel 1-alkyl-3-indolyl Z-aminoethyl ketones, a1-alkyl-3-acylindole is reacted with an aliphatic aldehyde and a basicnitrogen compound as represented by ammonia, or a primary or secondaryamine, in the presence of an inert solvent. It is preferred to employequimolar quantities of reactants although other quantities can also beemployed, if desired. The reaction is generally carried out under acidcondition, Le, a pH of less than seven. Various aliphatic aldehydes canbe employed, e.g., aqueous formaldehyde, paraformaldehyde, acetyldehyde,butyraldehyde, isobutyraldehyde, valeraldehyde, and the like. Inertsolvents can include methanol, ethanol, and isoamyl alcohol althoughwhen aqueous formaldehyde is employed no additional solvent isnecessary. Various primary and secondary amines can be employed in thereaction such as the primary or secondary alkyl, cycloalkyl, aralkyl,and aryl amines, as well as heterocyclic amines. Representative aminesinclude methylamine, dimethylamine, ethylamine, diethylamine,diisopropylamine, benzylamine, dibenzylamine', aniline, methylaniline,allylamine, piperidine, thiamorpholine, pyrrolidine, morpholine, and thelike.

The acid conditions generally necessary fo completion of the reactioncan be brought about by adding the amine as an acid addition salt suchas the hydrochloride, sulfate, hydrobromide, and the like. The acidconditions can also be brought about by the addition of an acid such asacetic, hydrochloric, phosphoric, sulfuric, hydrobrornic, and the like,to the reaction mixture.

The reaction is carried out at a temperature between about fifty andabout 100 degrees centigrade, advantageously at a temperature betweenabout 65 and about 85 degrees centigrade. The reaction is generallycompleted after a period of about 24 hours.

In carrying out the process of the present invention for the preparationof the novel l-aminomethyl-S-indolyl 2- aminoethyl ketones, al-hydro-3-acylindole is reacted with an aliphatic aldehyde and a basicnitrogen compound as represented by ammonia or a primary or secondaryamine, employing substantially the same reaction conditions noted above.In those instances wherein a 1-hydro-3- acetylindole is employed as thestarting compound it is.

necessary that at least twice the molar amount of an aliphatic aldehydeand basic nitrogen compound based on the starting 1-hydro-3-acetylindolebe employed, In those instances wherein the starting compound is otherthan a 1-hydro-3-acetylindole it has surprisingly been found that thereaction will proceed even when the amounts of aliphatic aldehyde andbasic nitrogen compound are much less than noted above, e.g., thedesired l-aminomethyl-3- indolyl Z-aminoethyl ketones are obtained byutilizing equimolar amounts of starting reactants. However, in order toimprove the overall yield it is generally preferable to employ at leasttwice the molar amount of an aliphatic aldehyde and basic nitrogencompound based on the starting l-hydro-3-acylindole.

The novel 1-hydro-3-indolyl Z-aminoethyl ketones of the presentinvention can be prepared by subjecting a 1-aminomethyl-3-indolylZ-aminoethyl ketone to alkaline hydrolysis utilizing, for example,potassium hydroxide, sodium hydroxide, sodium carbonate, or potassiumcarbonate, and the like. The alkaline hydrolysis results in a cleavageof the l-aminomethyl substituent.

Alternatively, the l-hyclro-3-acetylindoles can be employed as directstarting compounds for the preparation of the corresponding1-hydro-3-indolyl Z-aminoethyl ketones. This can be most advantageouslyaccomplished by utilizing equimolar quantities of reactants or byemploying at least one of the other reactants (i.e., aliphatic aldehydeand basic nitrogen compounds) in an amount not substantially greaterthan equimolar based on the starting 1-hydro-3-acetylindole.

The thus-produced 3-indolyl 2-aminoethyl ketones can be recovered in aconventional manner from the reaction mixture. For example, the3-indolyl Z-aminoethyl ketone acid addition salt precipitate can berecovered by filtration after cooling the reaction mixture. The freebase can be recovered by dissolving the acid addition salt in water,extracting with ether, and adding excess alkali-metal hydroxide to theaqueous mixture. The resulting mixture can be extracted with ether andthe ether extracts washed with a saturated salt solution. The washedproduct can thereupon be dried and the resulting dried mixtureevaporated and triturated to produce the free base.

, In some instances the acid addition salt is extremely soluble and willnot readily precipitate upon cooling from the reaction mixture. In suchcases, however, the acid addition salt can be recovered by evaporatingthe reaction solvent, adding water to the resulting reaction mixture,extracting the reaction mixture with ether, adding a cold solution of analkali-metal hydroxide to the aqueous solution, extracting withchloroform, drying the chloroform extract over sodium sulfate, andevaporating the chloroform. The acid addition salt can then be isolatedby adding the desired acid (e.g., hydrochloric, hydrobromic, sulfuric,acetic, tartaric, citric, and the like) to a chloroform solution of thefree base,

The 3-indolyl 2-aminoethyl ketone N-oxides can be prepared by reactingthe tertiary amine free base with an oxidizing agent such as hydrogenperoxide, peracetic acid, and 3-indolyl Z-aminoethyl ketone N-oxide acidaddition salts can be prepared by reacting a 3-indolyl 2- aminomethylketone N-oxide dissolved, e.g., in ethyl alcohol-ethyl acetate, with anacid such as hydrochloric, hydrobromic, sulfuric, acetic, tartaric,citric, and the like.

The 3-indolyl Z-aminoethyl ketones can also be converted to novel anduseful quaternary ammonium salts by reacting the tertiary amine freebase in an inert solvent with a suitable quaternary ammoniumsalt-forming compound such as methyl iodide, ethyl bromide, octylbromide, benzyl chloride, dimethyl sulfate, methyl paratoluenesulfonate, and the like. The 3-indolyl Z-aminoethyl ketone quaternaryammonium salts can for the most part be represented by the followinggeneral formula:

wherein X, R, R and R have the same values represented above. R and Rtaken individually represent aryl, aralkyl, and alkyl and togethercontain not more than fifteen carbon atoms, and when taken together with7 tains not more than eight carbon atoms and Y represents an anion, suchas a halogen anion, e.g., a chloride, iodide, or bromide anion; asulfate anion, e.g., that derived from dimethyl sulfate; apara-toluenesulfonate anion, e.g., that derived from methylpara-toluenesulfonate, and the like.

The 2-, 4-, 5-, 6-, and 7-positions can similarly be substituted asnoted above.

The S-indolyl Z-aminoethyl ketones produced by the novel process of thepresent invention have hypotensive and diuretic activity. In addition,the l-alkyl-3-indolyl Z-aminoethyl ketones and l-hyclro-3-indolylZ-aminoethyl ketones can be converted by lithium aluminum hydride topharmacologically active 3-(3-aminopropyl)-indoles, e.g.,3-(3-dirnethylaminopropyl)-indole can be produced by reducingZ-dimethylaminoethyl 3-indolyl ketone with lithium aluminum hydride intetrahydrofuran. The 3-(3- aminopropyl)-indo-les also have hypotensiveactivity.

Furthermore, the 3-indolyl 2-aminoethyl ketones can be reacted withfiuosilicic acid to form the fluosilicate salts which in dilute aqueoussolutions are effective mothproofing agents as more fully disclosed inUS. Patents 2,075,359 and 1,915,334.

The novel 3-indolyl 2-aminoethyl ketone quaternary ammonium salts can beemployed as intermediates for the preparation of auxins (plant growthsubstances, e.g., Z-dimethylaminoethyl 3-indolyl ketone methiodide canbe reacted with sodium cyanide to produce 3-(y-cyanopropionyl)-indole,the latter subjected to alkaline hydrolysis to produce the keto acid,and the latter reduced utilizing the procedure of Huang-Minion [1. Am.Chem. Soc. 68, 2487 (1946)] to produce 3-indolebutyric acid(Agricultural Chemistry, Frear, vol. 1, page 427, 1952, D. Van NostrandCo.). The Huang-Minlon technique involves refluxing the ketone withdiethylene glycol, hydrazine hydrate, and sodium hydroxide, distillingoi the water and hydrazine hydrate to raise the temperature to to 200degrees centigrade and refluxing again for three to four hours.Alternatively, 3-indolebutyric acid can also be produced by subjectingthe keto acid to hydrogenolysis utilizing five percent palladium onc-arbon in alcohol.

Moreover, the 1-alkyl-3-indolyl Z-aminoethyl ketones aoszosr EXAMPLEl.2-DIBENZYLAMINOETHYL 3- INDOLYL KETONE A. Z-Dibenzylaminoerhyl3-Indolyl Ketone Hydrochloride A mixture of 4.35 g. of S-indolyl methylketone (Saxton, J, Chem. Soc. 1952, 3592), 6.4 g. of dibenzylaminehydrochloride, 1.23 g. of paraformaldehyde and 41 ml. of absoluteethanol was refluxed for 24 hours. The solution was cooled to about 25C. and crystallization thereupon occurred. The cooled mixture wasfiltered and the precipitate was washed with methanol and ether to yieldZ-dibenzylaminoethyl 3-indolyl ketone hydrochloride which melted at 189to 189.5 C.

Anal.Calcd. for C H N OCI: Cl, 8.76. Found: Cl, 8.85.

B. Z-Dibenzylamz'noethyl 3-Ind0lyl Ketone Free Base The hydrochloridefrom Part A was dissolved in water and extracted with ether. Excesspotassium hydroxide was added to the aqueous mixture and the resultingmixture was extracted with ether. The resulting ether extract was washedwith saturated sodium chloride solution, dried over anhydrous sodiumsulfate, and evaporated to produce an oil. The resulting oil wastriturated with ether-petroleum ether and recrystallized frombenzenepetroleum ether to produce Z-dibenzylaminoethyl 3-indolyl ketonefree base which melted at 130.5 to 132 C.

Anal.Calcd. for C H N O: C, 8l.49; H, 6.97; N, 7.61. Found: C, 81.38; H,6.35; N, 7.78.

EXAMPLE 2.DIMETHYLAMINOETHYL 3-(5 BENZYLOXYINDOLYL) KETONE A.3-(5-Benzyl0xyind0lyl) Methyl Ketone S-benzyloxyindole (11.15 g.; 0.05mole) dissolved in 100 ml. of ether and 100 ml. of benzene was addedduring five minutes to a Grignard reagent prepared from magnesium (2.68g.; 0.11 mole) and methyl iodide (17 g.; 0.12 mole). The mixture wasrefluxed for 75 minutes. It was then cooled in ice and 8.65 g. (0.11mole) of acetyl chloride in 25 ml. of ether was added dropwise. Theresulting mixture was stirred for three hours at about 25 C The m xturewas then cooled in ice and acidified with a solution of 15 ml. of aceticacid in 50 ml. of water. After stirring for 15 minutes the precipitatewas filtered, washed with water and ether and suspended in 50 ml. ofethanol. A solution of 3 g. of potassium hydroxide in 10 ml. of waterwas added and the resulting solution was evaporated to about half itsvolume to yield 5.95 g. of 3-(5-benzyloxyindolyl) methyl ketone whichwas recrystfllized from ethanol and melted at 188l90 C, Infrared andultraviolet spectra were in accord with the proposed structure. Thefiltrate was evaporated further to yield an additional quantity of3-(5-benzyloxyindolyl) methyl ketone.

Anal.Calcd. for C H NO C, 76.96; H, 5.70; N, 5.28. Found: C, 77.36; H,5.43; N, 5.39.

B. Z-Dz'methylaminoethyl 3-(5-Benzyl0xyind0lyl) Ketone Hydrochloride Amixture of 2.65 g. of 3-(5-benzyloxyindolyl) methyl ketone (0.01 mole),0.98 g. of dimethylamine hydrochloride (0.012 mole), 0.6 g. ofparaformaldehyde and ml. of absolute ethanol was refluxed for 26 hours.Crystals appeared after a few hours of refluxing. The mixture wasallowed to stand for 12 hours and was then cooled in ice, filtered, andwashed with cold methanol and ether to yield 2.48 g. ofZ-dimethylaminoethyl 3-(5-benzyloxyindolyl) ketone hydrochloride. Thehydrochloride was recrystallized twice by dissolving in 75 ml. ofabsolute 6 ethanol and evaporating to 40 ml "Ihe recrystallizedhydrochloride melted at 199.5-200.5 C.

Anal.Calcd. for C H N O Cl: C, 66.93; H, 6.46; N, 7.81; Cl, 9.88. Found:C, 67.36; H, 6.86; N, 8.05; Cl, 9.82. I

C. Z-Dimethylaminoethyl 3-(5-Benzyl0xyind0lyl) Ketone Free Base Thehydrochloride from Part B was reacted with potassium hydroxide in thesame manner as shown in Example I, Part B, to produce2-dimethylaminoethyl 3-(5- benzyloxyindolyl) ketone free base.

EXAMPLE 3.-2-DIMETHYLAMINOETHYL 3-INDOLYL KETONE A. Z-Dimethylaminoethyl3- lndo lyl Ketone Free Base A mixture of 3-indolyl methyl ketone (15.9g.; 0.1 mole), dimethylamine hydrochloride (8.15 g.; 0.1 mole),paraformaldehyde (4.5 g.; 0.15 mole) and ml. of absolute ethanol wasrefluxed for 24 hours. The clear brown solution was allowed to stand at25 C. for 24 hours and was then evaporated under vacuum to a viscousoil. Water (200 ml.) was added and the mixture was filtered. The aqueousfiltrate was extracted twice with ether. The clear aqueous solution wasthen cooled in ice and made alkaline with a cold solution of potassiumhydroxide (10 g.) in 25 ml. of water. The resulting oil was extractedthrice with chloroform and the chloroform extracts were washed twicewith saturated sodium chloride solution, and dried over anhydrous sodiumsulfate. The chloroform was removed by evaporation to produce 13.1 g. of2-dimethylaminoethyl 3-indolyl ketone free base. The compound melted at116 to 118.5 C. and had the following analysis:

AnaL-Calcd. for C H N O: C, 72.19; H, 7.46; N, 12.96. Found: C, 72.37;H, 7.28; N, 12.72.

B. Z-Dimethylaminoethyl 3-Ind0lyl Ketone Hydrochloride To a chloroformsolution of Z-dimethylaminoethyl 3-indolyl ketone free base was addedgaseous hydrogen chloride and the resulting precipitate,Z-dimethylaminoethyl 3-indolyl ketone hydrochloride, melted at 179-l80C. and had the following analysis:

Anal.Calcd. for C H CIN O: C, 61.77; H, 6.78; (:1, 14.03; N, 11.09.Found: o, 61.36; H, 6.93; 01, 13.97; N, 10.69.

C. Z-Dimethylaminoethyl 3-Ind0lyl Ketone Meihiodide Methyl iodide (1.42g.; 0.01 mole) was added to a solution of 1.08 g. ofZ-dimethylarninoethyl 3-indoly1 ketone free base, in 6 ml. of methanolcooled in ice. The mixture was allowed to stand in the cold for fourhours. The mixture was filtered and the precipitate washed with coldmethanol to produce 1.53 g. of 2-dimethylaminoethyl 3-indolyl ketonemethiodide which melted at 2055-2075 C. (87 percent yield).

AnaL-Calcd. for C H N IO: C, 46.94; H, 5.35; N, 7.82; I, 35.43. Found:C, 47.03; H, 5.50; N, 7.58; I, 35.39.

EXAMPLE 4.-3-(3-DIMETHYLAMINOPROPYL)- INDOLE A solution of2-dimethylaminoethyl 3-indolyl ketone hydrochloride, Example 3, part B(1 g. in 10 ml. of tetrahydrofuran), was added to a suspension oflithium aluminum hydride (0.5 g.) in 25 ml. of tetrahydrofuran. Themixture was stirred for 15 minutes at 25 C. and refluxed for 1.5 hours.The mixture was allowed to stand for twelve hours and thereupon waterand 50 ml. of 10 percent potassium hydroxide solution was added. Themixture was extracted three times with methylene chloride. The combinedextracts were washed with ten percent sodium chloride solution, driedover anhydrous sodium sulfate and evaporated. The resulting oil wascrystallized from benzene-petroleum ether and was recrystallized fromSkellysolve B (mixture of hexanes) to produce 3-(3-dimethylaminopropyl)-indole which melted EXAMPLE 5.-3-INDOLEBUTYRIC ACID A solution ofsodium cyanide (0.735 g.) in 8 ml. of water was added to a suspension of1.52 g. of Z-dimethylaminoethyl 3-indo1yl ketone methiodide, prepared asdisclosed in Example 3, part C, in 8 ml. of methanol. A slow stream ofnitrogen was bubbled through the solution during the reaction. All thematerial dissolved in about one-half hour and crystallization started.The reaction was allowed to proceed for 19 hours. An equal volume ofwater Was then added, and the product, 3-( cyanopropionyl)-indole, wasfiltered and washed with water. The product weighed 0.5 gram (59.6percent yield), and melted at 206-211" C. Two recrystallizations frommethanol aiforded pale yellow needles which melted at 212-214 C.

AnaL-Calcd. for C H N O: C, 72.75; H, 5.09; N, 14.14. Found: C, 72.52;H, 4.90; N, 14.38.

The ketocyanide was hydrolyzed with aqueous methanolic alkali to-y-(3-indolyl)-'y-oxo-butyric acid, melting point 235238 C. (fromacetone).

Anal.Calcd. for C H NO C, 66.35; H, 5.11; N, 6.45. Found: C, 66.35; H,5.14; N, 6.26.

The 'y-(3-indolyn)-y-oxo-butyric acid was reduced utilizing theHuang-Minlon technique (loc. cit.) to pro duce 3-indolebutyric acid.

EXAMPLE 6.2-DIBENZYLAMINOETHYL 3-IN- DOLYL KETONE ETHIODIDE In the samemanner as shown in Example 3, part C, Z-dibenzylaminoethyl 3-indolylketone ethiodide was prepared by reacting Z-dibenzylaminoethyl 3-indoly1ketone free base (Example 1, part B) with ethyl iodide.

EXAMPLE 7.-2-DIMETHYLAMINOETHYL 3-(5- BENZYLOXYINDOLYL) KETONE BENZYLCHLORIDE In the same manner as shown in Example 3, part C,2-dimethylaminoethyl 3 benzyloxyindolyl) ketone benzyl chloride wasprepared by reacting Z-dimethylaminoethyl 3-(5-benzyloxyindolyl) ketonefree base (Example 2, part C) with benzyl chloride.

EXAMPLE 8.-2-DIMETHYLAMINOETHYL 3-IN- DOLYL KETONE N-OXIDE EXAMPLE 9.-2-DIMETI-IYLAMINOETHYL 3-IN- DOLYL KETONE N-OXIDE HYDROCHLORIDEZ-dimethylaminoethyi 3-indolyl ketone N-oxide hydrochloride was producedby dissolving 2-dimethylaminoethyl 3-indolyl ketone N-oxide, Example 8,in ethyl alcohol-ethyl acetate and passing gaseous hydrogen chlorideinto the mixture.

EXAMPLE 10.2-DIMETHYLAMINOETHYL 3-(1- METHYLINDOLYL) KETONE A.Z-Dimezhylaminoethyl 3-(1-Methylind0lyl) Keione Hydrochloride A mixtureof 13.6 g. of 1-methyl-3-acetylindole [C.A. 49, 1006 (1955)], 6.4 g. Ofdimethylamine 'hYdl'OChlO- ride, 3.54 g. of paraformaldehyde, and ml. ofethanol was refluxed for 24 hours. The solution was evaporated undervacuum and the resulting crude solid was recrystallized twice frommethanol to yield Z-dimethy-laminoethyl 3-(1-methylindolyl) ketonehydrochloride which melted at -186" C.

Anal.Calcd. for C H N ClO: C, 63.03; H, 7.35; N, 10.50; C1, 13.29.Found: C, 62.81; H, 6.93; N, 9.96; Cl, 13.33.

B. Z-Dimethylaminoethyl 3-(l- Methylind'olyl) Ketone Free Base In thesame manner as shown in Example 1, part B, 2- dimethylaminoethyl3-(1-methylindolyl) ketone free base was prepared by reactingZ-dimethylarninoethyl 3-(1- methylindolyl) ketone hydrochloride withpotassium hydroxide.

C. Z-Dimethylamz'noethyl 3-(1-Methylind0lyl) Ketone Metlzioa'ide In thesame manner as shown in Example 3, Part C, Z-dimethylaminoethyl 3-(lmethylindolyl) ketone methiodide was prepared by reactingZ-dimethylaminoethyl 3- (l-methylindolyl) ketone free base with methyliodide.

D. Z-Dimethylam-inoethyl 3-(1-Methylind0lyl) Ketone N-Oxide In the samemanner as shown in Example 8, Z-dimethylaminoethyl 3-(1-methylindolyl)ketone N-oxide was prepared by reacting 2-dimethylaminoethyl3-(1-methylindolyl) ketone free base with hydrogen peroxide.

'E. Z-Dimethylaminoethyl 3-(1-Methylind0lyl) Ketone N-OxideHydrochloride Z-dimethy-laminoethyl 3-(1-methylindolyl) ketone N- oxidehydrochloride was prepared by dissolving Z-dimethylaminoethyl3-(1-methylindolyl) ketone N-oxide in ethyl alcohol-ethyl acetate andpassing gaseous hydrogen chloride into the mixture.

EXAMPLE ll.-l DI-METHY-LAMINOETHYL-3-IN- DOLYL1-METHYL-2-DIMETHYLAMINOE'I'HYL KETONE A.1-Dimethylamin0methyl-3-Ind0lyl l-Methyl-Z-Dimethylaminoethyl KetoneFree Base 3-propionylindole was prepared in the same manner disclosed inExample 2A by substituting indole and propionyl chloride forS-benzyloxyindole and acetyl chloride.

A mixture of 3.46 g. of 3-propionylindole (0.02 mole), 8.16 g. ofdimethylamine hydrochloride (0.1 mole), 4.5 g. of paraformaldehyde (0.15mole) and 70 ml. of absolute ethanol was refluxed for 28 hours. Themixture was evaporated to about 15 ml. and water was added whichresulted in a precipitate consisting essentially of unchanged3-propionylindole. The mixture was filtered and the filtrate wasextracted twice with chloroform. The aqueous layer was made basic withten percent aqueous potassium hydroxide solution and extracted withchloro form. The chloroform extracts were washed with saturated sodiumchloride solution, dried over anhydrous sodium sulfate and evaporated togive 1.5 g. of 1-dimethylaminomethyl-S-indolyl.1-methyl-Z-di-methylaminoethyl ketone free base as a yellow oil.

B. 1-Dimethylamin0methyl-3-Ind0lyl .l-Methyl-Z-Dimethylaminoethyl KetoneDihydrochloride The 1-dimethylaminomethyl-3-indolyl1-methyl-2-dimethylaminoethyl ketone free base of Part A was dissolvedin ether and an ethereal solution of hydrogen chloride was added. Theprecipitated dihy-drochloride was purified by dissolving in fivemilliliters of methanol, and successively adding twenty milliliters ofacetone and eighty milliliters of anhydrous ether. The yield ofl-dimethylaminomethyl-3-indolyl 1-methyl-2-dimethylaminoethyl ketonedihydrochloride thus obtained was 1.3 g. and the compound melted at187-190 C.

EXAMPLE 12.1 DIM-ETHYLAMINOMETHYL-3- INDOLYL Z-DIMETHYLAMINOETHYL KETONEA. J-Dimethylaminomethyl-3-Indolyl Z-Dimethylaminoethyl Kezone Free BaseA mixture of 31.8 g. of 3-indolyl methyl ketone (0.2 mole), 81.55 g. ofdimethylamine hydrochloride (1.0 mole), and 45.6 g. of paraformaldehyde(1.52 moles) in 705 ml. of absolute ethanol was refluxed for 21 hours. Aclear solution was obtained after two hours. The solution was thenevaporated on the steam bath to give a light brown oil. 500 ml. of waterwas added, the solution was cooled in ice, and made basic (pH 89) withaqueous potassium carbonate solution. The mixture was extracted threetimes with ether (total 700 ml.). The ethereal solution was washed oncewith water, once with saturated sodium chloride solution, dried overanhydrous sodium sulfate and evaporated to produce 39.3 g. of oilyl-dirnethylamino-methyl-3-indoly-l Z-dimethylaminoethyl ketone freebase.

Anal.Calcd. for C H N O: C, 70.29; H, 8.48; N, 15.37; N. E., 136.69.Found: C, 69.79; H, 8.78; N, 15.01; N. B, 141.40.

B. I-Dimethylaminomethyl-3-Ind0lyl Z-Dimethylaminoethyl KetoneDihydrochloride In the same manner as disclosed in Example 11, Part B,l-dirnethylaminomethyl 3 indolyl Z-dimethylaminoethyl ketonedihydrochloride was produced utilizing l-dimet-hylaminomethyl-S-indolylZ-dimethylaminoethyl ketone free base in lieu of1-dimethylaminomethyl-3-indolyl 1-methyl 2-di-methylaminoethyl ketonetree base. The resulting compound melted at 184187 C.

Anal.-Calcd. for C H N OCl C, 55.49; H, 7.28; N, 12.13; Cl, 20.48; N.E.,173.1. Found: C, 54.72; H, 7.66; N, 12.41; Cl, 20.51; N.E., 182.2.

EXAMPLE 13.3-INDGLYL l-METHL-Z-DIMETH- YLAMINOETHYL KETONE FREE BASE Asolution of 1.95 g. of potassium hydroxide in 5 ml. of water was addedto a solution of l-dimethylaminoethyl-3-indolyl1-rnethyl-2-dimethylaminoethyl ketone free base, Example 11, part A, in12.5 ml. of methanol and the resulting solution was refluxed forone-half hour. The mixture was evaporated on the steam bath under vacuumand 20 ml. of water was then added. The resulting mixture was extractedthree times with a total of 50 ml. of chloroform. The chloroformextracts were washed once with water and then three times withhydrochloric acid (20, 10 and 10 ml. portions). The combined acidextracts were washed once with 10 ml. of chloroform and then poured intoan ice-cold solution of ml. of aqueous potassium hydroxide solution. Theresulting mixture was extracted three times with ether (total 150 ml.).The combined ethereal extracts were washed once with water, once withsaturated sodium chloride solution, dried over anhydrous sodium sulfateand evaporated to give 0.543 g. of a yellow glassy solid. The productwas recrystallized from a mixture of 3 ml. of ethyl acetate and 9 ml. ofpetroleum ether; 0.265 g. of 3-indolyl 1-methyl-2-dimethylaminoethylketone free base was thus obtained. The compound melted at 101-102 C.

Anal.-Calcd. for C H N O: C, 73.01; H, 7.88; N, 12.12; N.E., 230.3.Found: C, 72.99; H, 7.61; N, 11.74; N.E., 234.9.

The compound of this example when administered intraperitoneally to miceat a dosage of 20% of the LD gave a 784% sleeping-time increase in thestandard hexobarbital sleeping test. At half this dosage the timeincrease was 683%; at A the dosage the time increase was 216%.

1 0 EXAMPLE 14.-1-D1METHYLAMINOETHYL 3-IN- DOLYL 1 ETHYL-ZDIMETHYLAM-INOETHYL KETONE FREE BASE A mixture of 6.77 g. (0.0362 mole)of 3-butyrylindole (Oddo et al., Beilstein 21,303), 14.8 g. (0.181 mole)of diinethylamine hydrochloride, 8.2 g. (0.273 mole) paraforma-ldehydeand 135 ml. of absolute ethanol was refluxed for 26 hours. The resultingyellow solution was evaporated on the steam bath and 60* ml. of waterwas added. The mixture was then filtered and the filtrate was extractedwith three 50 ml. portions of ether, the remaining filtrate was cooledin ice, and then made basic with a solution of potassium carbonate (19'g. in 39 ml. of water). The mixture was extracted three times with 60ml. portions of ether. The combined ether extracts were washed withwater and then with saturated sodium chloride solution, dried overanhydrous sodium sulfate, and evaporated under vacuum to produce 2.94 g.of yellow oil which solidified after 12 hours. The product wasrecrystallized from isopropyl ether to produce 0.33 g. ofl-dimethylaminoethyl-3-indolyl 1-ethyl-2-dimethylaminoethyl ketone freebase which melted at 7880 C.

Anal.Calcd. for C H N Oz N, 13.99; N.E., 150.71. Found: N, 13.72; N.E.,149.00.

EXAMPLE 15 .l DIMETHYLAMINOMETHYL 3- TNDOLYL 1,1-D1METHYL-2DIMETHYLAMINO- ETHYL KETONE A. 1-Dimezhylamin0methyl-3-Indolyl1,1-Dimethyl-2- Dimethylaminoethyl Ketone Free Base 3-isobutyrylindolewas prepared in the same manner as disclosed in Example 2, part A, bysubstituting indole and isobutyryl chloride for S-benzyloxyindole andacetyl chloride. 3

A mixture of 6.3 g. (0.0337 mole) of 3-isobutyrylindole, 13.8 g. (0.169mole) of dirnethylamine hydrochloride, 7.63 g. (0.254 mole) ofparaformaldehyde and 126 ml. of absolute ethanol was refluxed for 24hours. The resulting colorless solution was evaporated on the steam bathunder vacuum. Sixty ml. of water was added and the mixture was filtered.The aqueous filtrate was extracted 3 times with 50 ml. portions of etherand then made basic with a solution of potassium carbonate (17.8 g. in32 ml. of water). The alkaline solution was extracted 3 times with 60ml. portions of ether. The combined ether extracts were washed withwater and then with saturated sodium chloride solution, dried overanhydrous sodium sulfate and evaporated under vacuum. The resulting oil,1-dimethylaminoethyl-3-indolyl 1,1-dimethyl-2-dimethylaminoethyl ketonefree base, weighed 1.6 g.

B. I-Dimethylamin0ethyl3-Ind0lyl 1,1-Dimethyl-2- DimethylaminoethylKetone D ihydrochloride The oil of part A,1-dimethylaminomethyl-3-indolyl 1,1- dimethyl-Z-dimethylarninoethylketone free base, was dissolved in ether and converted tol-dimethylarninornethyl- 3-indolyl 1,1-dimethyl-Z-dimethylaminoethylketone dihydrochloride with ethereal hydrogen chloride in the samemanner disclosed in Example 11, part B.

EXAMPLE 16.-l-ETHYL-3-INDOLYL 2-DIMETHYL- AMINOETHYL KETONE A.I-EthyV-S-Indolyl ZDimefhylaminoethyl Ketone Free Base A mixture of49.32 of 1-ethy'l-3-acetylindole (0.264 mole), 25.8 g. of dimethylaminehydrochloride (0.316 mole), and 15.85 g. of paraformaldehyde (0.528mole) in 400 ml. of absolute ethanol was refluxed for 19 hours. Theresulting solution was evaporated to dryness on the steam bath undervacuum. The residue was dissolved in 350 ml. of water and extractedtwice with ether. The brown aqueous solution was cooled in ice and madebasic with a solution of potassium hydroxide (33.6 g. in

11 ml. of water). The mixture was extracted three times with ether. Thecombined ethereal extracts were washed with saturated sodium chloridesolution, dried over anhydrous sodium sulfate and evaporated to give 56g. of 1-ethyl-3-indolyl Z-dimethylaminoethyl l etone free base.

B. l-Ethyl-S-Indolyl Z-Dimezhylaminoethyl Ketone Methiodide AnaL-Calcd.for C H IN O: C, 49.75; H, 6.00; I, l

EXAMPLE 17.1-METHYL-3-INDOLYL l-METi-IYL- Z-DIMETHYLAMINO-ETHY L KETONEA. 1-Methyl-3-Pr0pi0nylindole A suspension of 51 g. of 3-propionylindole(0.295 mole) in 530 ml. of water and 52 g. of sodium hydroxide washeated to 70 C. on the steam bath. Heating was discontinued and 56 ml.of dimethyl sulfate was added during five minutes. Addition of dimethylsulfate and sodium hydroxide was repeated two more times and the mixturewas then heated at 95 C. for 2.5 hours. The oily layer solidified after12 hours. The solid was recovered by filtration and washed with water.The product was dissolved in 800 ml. of ether, filtered from a brownimpurity, and evaporated until crystallization started. The product,1-methyl-3-propionylindole, weighed 40.15 g. and melted at 8081.5 C.

Anal.-Calcd. for C H NO: C, 76.97; H, 7.00; N, 7.48. Found: C, 77.00; H,6.80; N, 7.73.

B. 1-Methyl-3-Indolyl 1-Methyl-2-Dimethylamin0etityl' Ketone Free BaseFound: C, 49.61; H, 6.09; I, 32.51;

A mixture of 9.35 g. of 1-methyl-3-propionylindole (0.05 mole), 20.4 g.of dimethylamine hydrochloride (0.25 mole), 11.3 g. of paraformaldehyde(0.375 mole) and 175 ml. of absolute ethanol was refluxed for 21 hours.The mixture was evaporated to dryness and the resulting oily solid wastreated with 100 ml. of water, filtered, and washed with water. Theaqueous filtrate was extracted twice with 100 ml. portions of ether andwas then cooled in ice and made basic with a solution of 17 g. ofpotassium hydroxide in 50 ml. of water. The resulting mixture wasextracted three times with 350 ml. of ether. The combined extracts werewashed once with water, once with saturated sodium chloride solution,dried over anhydrous sodium sulfate and evaporated to give 4.0 g. of anoil which solidified on standing. The product, 1-methy1-3-indolyl1-methyl-2-dimethylaminoethyl ketone free base, was recrystallized fromSkellysolve B and melted at 79.5-80.5 C.

Anal.CalCd. for C15H N20: C, H, N,

11.47. Found: C, 74.00; H, 8.12; N, 11.48.

EXAMPLE 18.1,2-DIETHYL-3 -INDOLYL Z-ETHYL B. 1,2-Diethyl-3-Ind0lylZ-Erhyl-Z-Diethylaminethyl Ketone Hydrochloride In the same manner asdisclosed in Example 10, part 12 A, 1,2-diethyL3-indo1yl2-ethyI-Z-diethylaminoethyl ketone hydrochloride was prepared using1,2-diethyl-3-acetylindole, diethylamine hydrochloride, andpropionaldehyde in 'lieu of 1-methyl-3-acetylindole, dimethylaminehydrochloride and paraformaldehyde.

C. 1,2-Diethyl-3-Ind0lyl 2-Ethyl-2-Diethylaminoethyl Ketone Free Base Inthe same manner as disclosed in Example 1, part B, 1,2-diethyl-3-indolyl2-ethyl-2-diethylaminoethyl ketone free base was prepared by reacting1,2-diethyl-3-indolyl Z-ethyI-Z-diethylaminoethyl ketone hydrochloridewith potassium hydroxide.

D. 1,2-Dieihyl-3-Ind0lyl Z-EthyZ-Z-Diethylaminoethyl Ketone Ethiodide Inthe same manner as'shown in Example 3, part C, 1,2-diethyl-3-indolyl2-ethyl-2-diethylaminoethyl ketone ethiodide was prepared by reacting1,2-diethyl-3-indolyl Z-ethyl-Z-diethylaminoethyl ketone free base withethyl iodide.

EXAMPLE 19.1,2-DIPROPYL-6-(PARA,PARA'-DI- METHYLBENZHYDRYLOXY -3-INDOLYL 1,1-DI

ETHYL-Z-PIPERIDINOETHYL KETONE A.-1,2-Dipr0pyl-6-(Para,Para'-Dimethylbenzhydryloxy)- S-Indolyl1,1-Diethyl-Z-Piperidin0ethyl Ketone Hydrochloride B. 1,2DiprOpyl-6-(Para,Para'-Dimethylbenzhydryloxy) 3-Irzdolyl1,1DiethyI-Z-Piperidinoethyl Ketone Free Base In the same manner asdisclosed in Example 1, part B, 1,2 dipropyl6-(para,para'-dimethylbenzhydryloxy)-3- indolyl1,l-diethyl-2-piperidinoethyl ketone free base was prepared by reacting1,2-dipropyl-6-(para,para-dimethylbenzhydryloxy) -3 -indolyl1,1-diethyl-2-piperidinoethyl ketone hydrochloride with potassiumhydroxide.

C. 1,2 Dipr0pyl-6-(Para,Pam'-Dimethylbenzhydryloxy)- S-Indolyl1,1-Diethyl-Z-Piperidinoethyl Ketone Benzyl Chloride In the same manneras shown in Example 3, part C, 1,2dipropyl-6-(para,para-dimethylbenzhydryloxy)-3- indolyll,1-diethyl-2-piperidinoethyl ketone benzyl chloride was prepared byreacting 1,2-dipropyl-6-(para,paradimethylbenzhydryloxy)-3-indolyl I1,1-diethyl-2-piperidinoethyl ketone free base with benzyl chloride.

EXAMPLE 20.-1 (1 DIBUTYLAMINOAMYL)-6- ACETOXY-Bt-INDOLYL2-BUTYL-2-DIBUTYLAMI- NOETHYL KETONE A 6-Acet0xy-3-Acetylind0le In thesame manner as disclosed in Example 2, part A,6-benzyloxy-3-acetylindole was prepared utilizing 6-henzyloxyindole (J.Chem. Soc. 1937, 1726) in lieu of 5- benzyloxyindole.

The 6-benzyloxy-3-acetylindole was debenzylated according to theprocedure disclosed in US. Patent 2,708,- 197 to produce6-hydroxy-3-acetylindole. The resulting 6-hydroxy-3-acetylindole wasacetylated with acetic an- 13 hydride at about 25 C. to produce6-acetoxy-3-acetylindole.

B. 1-(1-Dibutylaminoamyl) -6-Acet0xy-3-Ind0lylZ-Butyl-Z-Dibutylaminoethyl Ketone Free Base In the same manner asdisclosed in Example 11, part A, l(l-dibutylaminoamyl)-6-acetoxy-3-indolyl 2-butyl- Z-dibutylaminoethylketone free base was prepared using 6-acetoxy-3-acetylindole,dibutylamine hydrochloride, and valeraldehyde in lieu of3-propionylindole, dimethylamine hydrochloride, and paraformaldehyde.

C. l(] -Dibutylaminamyl) -6-Acezoxy-3-Ind0lyl Z-Butyl-2-Dibutylaminoethyl Ketone Dihydrochloride The free base of part B wasdissolved in ether and treated with ethereal hydrogen chloride toproduce 1-(1- dibutylaminoamyl)-6-acetoxy-3-indolyl2-butyl-2-dibutylaminoethyl ketone dihydrochloride. The resultingdihydrochloride was purified by dissolving in methanol, and successivelyadding acetone and anhydrous ether.

D. I-(I-Dibutylaminoamyl) -6-Acet0xy-3-Ind0lyl 2-ButyZ-Z-Dibutylaminoethyl Ketone Bis-Ethiodide In the same manner asdisclosed in Example 13, 6-acetoxy-S-indolyl 2-butyl-2-dibutylaminoethylketone free base was prepared by alkaline hydrolysis utilizing 1-(1-dibutylaminoarnyl)-6-acetoxy-3-indolyl 2-butyl-2-dibutylaminoethylketone free base in lieu of l-dimethyl-aminomethyl-B-indolyl1-methyl-2-dimethy1aminoethyl ketone free base.

EXAMPLE 22.l (l BUTYLAMINOBUTYL) 7- METHOXY-Ia-INDOLYLLZ-DIPROPYL-Z-BUTYL- \AMINOETI-IYL KETONE A. 7-Methoxy-3-ValerylindoleIn the same manner as disclosed in Example 2, part A,7-methoxy-3-valerylindole was prepared utilizing 7- methoxy-indole (C.A.44, 6040) and valeryl chloride in lieu of S-benzyloxyindole and acetylchloride.

B. 1 -(1 -Bzztylamin0butyl)-7-Meth0xy-3-lnd0lyl 1,2-Di-Propyl-Z-Butylaminoethyl Ketone Free Base In the same manner asdisclosed in Example 11, part A, 1 (lbutylaminobutyl)-7-methoxy-3-indolyl 1,2-dipropyl-Z-butylaminoethylketone free base was prepared using 7-rnethoxy-3-valerylindole,butylamine hydrochloride and butyraldehyde in lieu of 3-propionylindole,dimethylamine hydrochloride, and paraformaldehyde.

C. 1 -(1 -Butylamin0butyl) -7-Meth0xy-3-Indolyl 1,2-Dipropyl-Z-Butylamin0ethyl Ketone Dihydrochloride The free base of partB was dissolved in ether and treated with ethereal hydrogen chloride to,produce 1-( l-butylaminobutyl) 7 methoxy-3-indolyl1,2-dipropyl-2-butylaminoethyl ketone dihydrochloride. The resultingdihydrochloride was purified by dissolving in methanol, and successivelyadding acetone and anhydrous ether.

EXAMPLE 23.-7-VIETHOXY-3-INDOLYL 1,2-DI- PROPYL-Z-BUTYLAMINO-ETHYLKETONE FREE BASE In the same manner as disclosed in Example 13, 7-rnethoxy-3-indolyl 1,2-dipropyl-2-butylaminoethyl ketone free base wasprepared by alkaline hydrolysis utilizing l( l-butylaminobutyl-7-methoxy-3 -indolyl 1,2-dipropyl- Z-butylaminoethyl ketone free basein lieu of l-dimethyl- 14 aminomethyl-3-indolyl l-methyl 2dimethylaminoethyl ketone free base.

EXAMPLE 24.1 DIPROPYLAMINOMETHYL 2- PHENYL-5-CHLORO-3 -INDOLYLl-METHYL-Z-DI- PROPYLAMINOETHYL KETONE A.2-Pheny[-5-Chl0r0-3-Propionylind0[e In the same manner disclosed inExample 2, part A, 2-phenyl-5-chloro-3-propionylindole was preparedusing Z-phenyl-S-chloroindole (J. Chem. Soc. 1948, 847) and propionylchloride in lieu of S-benzyloxylindole and acetyl chloride.

B. 1-Dipropylamin0methyI-Z-Phenyl-5-Chl01'0-3-Ind0lyl1-Methyl-2-Dipropylaminoethyl Ketone Free Base In the same manner asdisclosed in Example 11, part A,1-dipropylaminomethyl-Z-phenyl-S-chloro-3-indolyl 1-methyl-Z-dipropylaminoethyl ketone free base was prepared using2-phenyl-5-chloro-3-propionylindole and dipropylamine hydrochloride inlieu of 3-propionylindole and dirnethylamine hydrochloride.

C. 1-Dipr0pylamin0mezhyZ-Z-Phenyl-5-Chl0r0-3-Indolyl1-MethyZ-Z-Dipropylaminoethyl Ketone Dihydrochloride The base of part Bwas dissolved in ether and treated with ethereal hydrogen chloride toproduce l-dipropylaminomethyl-Z-phenyl-5-chloro-3-ind0lyll-methyl-Z-dipropylaminoethyl ketone dihydrochlon'de. The resultinghydrochloride was purified by dissolving in methanol, and successivelyadding acetone and anhydrous ether.

In the same manner as shown in Example 3, part C, 1 dipropylaminornethyl.2 phenyl-5-chloro-3-indolyl 1 methyl-2-dipropylaminoethyl ketonebis-methosulfate was prepared by reacting1-dipropylaminomethyl-2-phenyl- 5-chloro-3-ind0lyl1-methyl-2-dipropylaminoethyl ketone free base with 'dirnethyl sulfate.

EXAMPLE 25.2-PHENYL-5CHLORO -3 -INDOLYL 1-METHYL-2-DIPROPYLAMINOETHYLKETONE FREE BASE In the same manner as disclosed in Example 13, 2-phenyl-5-chloro-3-indolyl 1-methyl-2-dipropylaminoethyl ketone free basewas prepared by alkaline hydrolysis utilizing 1dipropylaminomethyl-2-phenyl-5-chloro-3-indolyl 1-methyl2-dipropylaminoethyl ketone free base in lieu of1-dimethylamin0methyl-3-indolyl l-methyl-Z-dimethylaminoethyl ketonefree base.

EXAMPLE 26.l-HEXYL 6 BENZYLOXY-3-INDO- LYL Z-BUTYL 2 METHYL-AMINOETHYLKE- TONE A. 1-Hexyl-6-Benzyl0xy3-Acetylindole In the same manner asdisclosed in Example 2, part A, 6-benzyloxy-3-acetylindole was preparedutilizing 6-benzyloxyindole in lieu of S-benzyloxyindole. The resulting6-benzyloxy-3-acetylindole was reacted with hexyl iodide in the mannerdisclosed by Baker, supra, to produce1-hexyl-6-benzyloxy-3-acetylindole.

B. 1-Hexyl-6-Benzyl0xy-3-lndolyl Z-Butyl-Z-Methyl- Aminoethyl KetaneHydrochloride In the same manner as disclosed in Example 10, part A,1-hexyl-6benzyloxy-3-indolyl 2-butyl-2-methylaminoethyl ketonehydrochloride was prepared using 1-hexyl-6- benzyloxy-3-acetylindole,methylamine hydrochloride and valeraldehyde in lieu of1-methyl-3-acetylindole, dimethylamine hydrochloride, andparaformaldehyde.

C. 1-Hexyl-6-Benzyl0xy-3-Ind0lyl 2-Butyl-2-Methyl- Aminoethyl KetoneFree Base In the same manner as disclosed in Example 1, part B,1-hexyl-6-benzyloxy-3-indolyl Z-butyl-Z-methylamino- 15 ethyl ketonefree base was prepared by reacting l-hexyl- 6-benzyloxy-3-indo1yl2-butyl2-methylaminoethyl ketone hydrochloride with potassium hydroxide.

The l-hexyl-6-benzyloxy-3-indolyl 2-butyl-2-methylaminoethyl ketone freebase was debenzylated utilizing palladium on charcoal in the mannerdisclosed in US. Patent 2,708,197 to produce 1-hexyl-6-hydroxy-3-indolyl2-butyl-2-methylarninoethyl ketone free base.

EXAMPLE 27.l-ETHYL-2-PHENYL-S-METHOXY- 3-INDOLYL 2 ETHYL 2MORPHOLINOETHYL KETONE A. 1Ethyl-2-Phenyl-5-Methoxy-3-Acetylindole Inthe same manner as disclosed in Example 2, part A,2-phenyl-5-methoxy-S-acetylindole was prepared utilizingZ-phenyl-S-methoxyindole (Bull. soc. chim. France, 1950, 551) in lieu ofS-benzyloxyindole. The resulting 2-phenyl-5-rnethoxy-3-acetylindole wasreacted with ethyl iodide in the manner disclosed by Baker, supra, toproduce l-ethyl-2-phenyl-5-methoxy-3-acetylindole.

B. 1-Ethy1-2-Phenyl-5-Methoxy-3-Ind0lyl Z-Ethyl-Z- MorpholinoethylKetone Hydrochloride In the same manner as disclosed in Example 10, partA, l-ethyl-2-phenyl-5-methoxy-3-indolyl 2-ethyl-2-morpholinoethyl ketonehydrochloride was prepared using 1-ethyl-2-phenyl-5-methoxy 3acetylindole, morpholine hydrochloride and propionaldehyde in lieu ofl-methyl- 3-acetylindole, dimethylamine hydrochloride, andparaformaldehyde.

C. ]-EthyZ-Z-Phenyl-S-Methoxy-3-Indolyl Z-Ethyl-Z- Moi'pholinoethylKetone Free Base In the same manner as disclosed in Example 1, part B,l-ethyl-2-phenyl-5-methoxy-3-indolyl 2-ethyl-2-rnorpholinoethyl ketonefree base was prepared by reacting I-ethyI-Z-phenyl-S-methoxy-S-indolylZ-ethyl 2 morpholinoethyl ketone hydrochloride with potassium hydroxide.

D. 1-EthyZ-Z-Phenyl-S-Meth0xy-3-Inal0lyl 2-Ezhyl-2- MorpholinoethylKetone Propyl Iodide In the same manner as shown in Example 3, part C,1-ethyl-2-phenyl-S-methoxy-3-indolyl 2 ethyl-2-morpholinoethyl ketonepropyl iodide Was prepared by reactingl-ethyl-Z-phenyl-S-methoxy-3-indolyl 2 ethyl-2-morpholinoethyl ketonefree base with propyl iodide.

EXAMPLE 28.2-ISOPROPY L 2 DIMETHYLAMI- NOETHYL 3-INDOLYL KETONE FREEBASE In the same manner as disclosed in Example 3, part A, butsubstituting isobutyraldehyde for paraformaldehyde,2-isopropyl-2-dimethylaminoethyl 3-indolyl ketone free base wasprepared.

In the same manner as disclosed above other 3-indolyl Z-aminoethylketones can be prepared utilizing the proper quantity of reactants asdisclosed above, for example,

1-(1-diethylaminoethyl)-6-benzyloxy-3-indolyl1,2-dimethyl-Z-diethylaminoethyl ketone free base,

6-benzyloxy-3-indolyl 1,2-dirnethyl-2-diethylaminoethyl ketone freebase,

1-butyl-3-indoly1 1-ethy1-2-pyrrolidinoethyl ketone hydrochloride,

S-indolyl l-rnethyl-1-ethyl-2-piperidinoethy1 ketone methiodide,

1-butyl-3-indolyl 1,Z-dibutyl-Z-morpholinoethyl ketone I hydrochloride,

1-( l-dibutylaminobutyl) -6-methoxy-3 -indolyl1,1,2-tripropyl-Z-dibutylarninoethyl ketone free base,

6-methoxy-3-indolyl 1,1,Z-tripropyl-Z-dibutylaminoethyl ketone freebase,

3-indolyl 1-methyl-Z-dimethylaminoethyl ketone hydrochloride,

S-indolyl 1-methyl-2-dimethylaminoethyl ketone hydrobromide,

3-indolyl 1-methyl-2-dimethylaminoethyl ketone sulfate,

16 S-indolyl 1-rnethyl-2-dimethylaminoethyl ketone acetate, 3-indo1yl1-methyl-2-dimethylaminoethyl ketone tartrate, 3-indolyll-methyl-Z-dimethylaminoethyl ketone citrate, 1- l-dibutylaminoamyl)-6-acetoxy-3 -indolyl 2-butyl-2- dibutylaminoethyl ketone bis(N-oxide),1-( 1-dibutylaminoamyl)-6-acetoxy-3-indolyl 2-butyl-2- dibutylaminoethylketone bis (N-oxide)dihydrochloride, and the like.

Z-aminoethyl ketones having the formula:

wherein X is selected from the group consisting of hydrogen, benzyloxy,halogen, alkoxy up to 9 carbon atoms, and acyloxy wherein the acylsubstituent is from an alkanoic acid of 1 to 8 carbon atoms, X isselected from the group consisting of hydrogen, alkyl of l to 8 carbonatoms, benzyl, and phenyl, R, R and R are selected from the groupconsisting of hydrogen and lower-alkyl of 1 to 4 carbon atoms, and R andR are selected from the group consisting of hydrogen, phenyl, benzyl,and alkyl of l to 4 carbon atoms and R and R together with -N form aheterocyclic amino selected from the group consisting of morpholinyl,piperidyl, pyrrolidyl, thiamorpholinyl and hexamethyleneimino whichcomprises the steps of heating at a temperature between about 50 andabout C. a l-hydro-B-acylindole wherein the 'acyl substituent is derivedfrom an alk-anoic acid of 2 to 10 carbon atoms and which contains ahydrogen atom alpha to the carbonyl group with an alkanal of 1 to 5carbon atoms and a basic nitrogen compound selected from the groupconsisting of ammonia, a primary amine, and a secondary amine, at 'a pHof less than seven, and further characterized inthat when R and R arehydrogen that at least twice the molar amount of alkanal and basicnitrogen compound based on the 1- hydro-3-acylindole are employed toproduce a l-aminomethyl-3-indoly1 2-arninoethyl ketone having the formula:

wherein X X R, R R R and R have the above values, and subjecting thethus produced l-aminornethyl- S-indolyl Z-aminoethyl ketone to alkalinehydrolysis to produce the desired 1-hydro-3-indolyl 2-aminoethyl k?-tone.

6. 1-amino-3-indolyl Z-aminoethyl ketone having the formula:

wherein X is selected from the group consisting of hydrogen, benzyloxy,hydroxy, halogen, alkoxy up to 9 carbon atoms, and acyloxy wherein theacyl substituent is from an alkanoic acid of 1 to 8 carbon atoms, X isselected from the group consisting of hydrogen, alkyl of '1 to 8 carbonatoms, benzyl, and phenyl, R, R and R are selected from the :groupconsisting of hydrogen and lower-alkyl of 1 to 4 cambon atoms, and R andR are selected from the group consisting of hydrogen, phenyl, benzyl,and 'alkyl of 1 to 4 carbon atoms and R and R together with -N form aheterocyclic amino selected from the group consisting of morpholinyl,piperidyl, pyrrolidyl, thiamorpholinyl, and hexamethyleneimino.

7. Quaternary ammonium compounds of the group consisting of those havingthe formula:

wherein X is selected firom the group consisting of hydrogen, benzyloxy,hydroxy, halogen, 'alkoxy up to 9 carbon atoms, and acyloxy wherein theacyl substituent is from an alkanoic acid of 1 to 8 carbon atoms, X isselected from the group consisting of hydrogen, alkyl of 1 to 8 carbonatoms, benzyl, and phenyl, R, R and R are selected from the groupconsisting of hydrogen and lower-alkyl of 1 to 4 carbon atoms, R and Rare selected from the group consisting of hydrogen, phenyl, benzyl, andalkyl of 1 to 4 carbon atoms and R and R together with -N form aheterocyclic amino selected from the group consisting of morpholinyl,piperidyl, pyrrolidyl, thiamorpholinyl and hexamethyleneimino, R isselected from the group consisting of benzyl and alkyl of not more thaneight carbon atoms, and Y is an anion selected from the group consistingof halogen, sulfate, and para-toluenesulfonate.

References Cited in the file of this patent UNITED STATES PATENTS2,814,625 Speeter Nov. 26, 1957 2,821,532 Anthony et a1. Jan. 28, 19582,849,454 Szmuszkovicz Aug. 26, 1958 2,877,234 Szmuszkovicz Mar. 10,1959 FOREIGN PATENTS 829,895 Germany Jan. 31, 1952 OTHER REFERENCESSalway: Jour. Chem. Soc., vol. 103, pages 351- (1913).

Organic Reactions, Adams, John Wiley and Son, New York, vol. 1, pages308-309 (1942).

UNITED STATES PATENT OFFICE CERTIFICATION OF CORRECTION PatentNo.3,037,991 June 5 1962 Jacob Szmuszkovicz It is hereby certified thaterror appears in the above numbered patent requiring correction and thatthe said Letters Patent should read as corrected below.

Column 1, lines 13 and 14, after "2-aminoethyl" insert ketone column 5,line 20, for "C H N OCl read C H N 0Cl --3 line 37, for"DIMETHYLAMINOETHYL" read 2-DIMETHYLAMINOETHYL column 10, line 1, for"l- DIMETHYLAMINOETHYL" read l-.-DIMETHYLAMINOMETHYL lines 21 and 49,for "l-dimethylaminoethyl", each occurrence, read l-dimethylaminomethylsame column 10, line 53, for "l-Dimethylaminoethyl" in italics; readl-Dimethylaminomethyl in italics; column 14, line 31, for"'lDipropylaminoethyl", in italics, read l-Dipropylaminomethyl initalics; column 17, line 1, for "l-amino-B-indolyl'Y readl-aminomethyl3-indolyl Signed and sealed this 16th day of October 1962.

(SEAL) Attest:

ERNEST W. SWIDER DAVID L. LADD Attesting Officer Commissioner of Patents

1. 1-DIMETHYLAMINOETHYL-3-INDOLYL 1-METHYL-2-DIMETHYLAMINOETHYL KETONE5. A PROCESS FOR THE PREPARATION OF 1-HYDRO-3-INDOLYL 2-AMINOETHYLKETONES HAVING THE FORMULA